The safe and effective delivery of an active agent(s) to a specific location enables a site-specific delivery that generally is associated with lesser side effects than more widespread delivery. Site-specific delivery is particularly desirable for the treatment of localized health conditions such as cancer, cardiovascular disease, orthopedic conditions, dental conditions, wounds and auto-immune diseases such as arthritis or gastrointestinal (G.I.) conditions. Such site-specific delivery is also desirable for the protection of inanimate products including marine, construction, and articles that are exposed to water and biological contamination, among others. The use of polymers for drug delivery began in the 1960s as controlled-release oral formulations of an agent coated with a non-therapeutic polymer. Many such formulations, however, induce inflammation or host responses at the delivery site, or have low and/or unpredictable potency, breakdown products, non-zero-order release rates, burst effects (drug delivery spikes), or other untoward effects.
Devices such as stents, grafts, implants, and surgical and wound healing devices frequently induce, or are associated with, undesirable side effects that include pain, inflammation, swelling, infection, adjacent tissue hyperproliferation, capsule, and foreign body response, such as granuloma or fibroma formation surrounding an implant. Although more biocompatible polymer coatings and other surface technologies were developed in order to reduce these effects, the polymers employed are either not biodegradable, or are inherently highly inflammatory and unpredictable in nature. Non-biodegradable coatings are disadvantageous, in addition, because they suffer from fatigue over time and they delaminate in situ.
Polymers containing therapeutic and other agents incorporated into a polymer backbone have been described for use in formulations and devices for use in medical and other applications. Many polymers, however, have limitations associated with, for example, adhesion (or lack thereof), and temperature dependency that detract from their performance. Most of the problems stem from lack of control over polymer structure and growth during the synthetic process. Up to now, the polymeric backbone had been formed by standard reaction mechanisms, such as the formation of a phenolic di-ester, and conversion to free aromatic diacids reacted to form a polymeric anhydride; known methods being represented by three main synthetic routes. In the first method, a mixed anhydride is prepared by reaction of a diacid with a low molecular weight aliphatic acid anhydride, e.g. acetic or propionic acid, and the mixed anhydride is heated under reduced pressure to form a polyanhydride in the molten state. Because of its low molecular weight, the acid anhydride may be discarded as a volatile by-product.
A second method involves reacting stochiometric amounts of an acid chloride of a diacid with a free diacid in the presence of an acid-acceptor, e.g. triethylamine, to generate a polyanhydride.
A third method relies on the polymerization-dehydration of a diacid with a dehydrating agent such as phosgene, diphosgene, triphosgene, or organophosphorus derivative, to obtain a pre-polyanhydride that is then polymerized.
Each of these methods, however, has disadvantages. The synthesis of polyanhydride-esters by melt condensation polymerization using a pre-polymer intermediate is generally conducted at high temperature, e.g. about 180 C, under vacuum. The increasing viscosity of the polymer melt as the reaction proceeds slows polymerization considerably and results in polymers of low molecular weight. Moreover, portions of the polymer melt undergo local decomposition due to the occurrence of localized high temperatures and incomplete mixing, and produce undesirable brownish polymers.
Certain applications require the use of resilient materials and tenacious films that require polymers of substantial molecular weight (MW), many times in excess of 100,000 Dalton. As is known in the art, the physical characteristics of a polymer depend on its molecular structure; discreet monomer units of regular structure tend to form crystalline or semi-crystalline materials, whereas polymers of irregular structure such as random copolymers tend to be amorphous. For other applications, polymers need to be solvent-cast into tough films or coatings, or molded under pressure into shaped articles, and then subjected to sterilization by ionizing radiation or electron beam bombardment, which seriously affect the polymer's molecular weight. It has heretofore been problematic to increase a polymer's molecular weight while retaining other desirable qualities. These polymers either fail to achieve a desired molecular weight, or form insoluble gels requiring extensive heating in the melt, or develop a high polydispersity index (MW/Mn), or both, due to the occurrence of side reactions. In the case of step-growth polymers, the polydispersity index (MW/Mn) often greatly exceeds a theoretical value of 2.0, possibly due to chain branching and/or interference from large ring macrocyclic oligomers.
Thus, there is a need for polymers, and for drug and other formulations and medical devices employing them, that exhibit a range of improved characteristics such as flexibility (or rigidity), adhesiveness, hardness, biocompatibility, processability temperature range, loading capacity, duration of delivery, and others, while at the same time limiting or avoiding one or more of the above described disadvantages. Many of these characteristics are achieved by producing high molecular weight polymers, and by careful control of the polymer structure and characteristics. In order to attain this goal, there is a need for novel synthetic processes that produces polymers of desired characteristics, in high yield, and with high purity.